In this article, urologists Scott E. Eggener, MD, and Stacy Loeb, MD, MSc, discuss the current applications for prostate cancer biomarkers and MRI, their impact on clinical practice, and future developments.
Men in the United States have about a 1 in 7 lifetime chance of being diagnosed with prostate cancer, but many of these men will have indolent disease that has a low likelihood of ever causing clinical symptoms. Now a number of diagnostic modalities are available that provide prognostic information to aid urologists and patients with decisions about biopsy and management of prostate cancer. These tools include a variety of urine-, blood-, and tissue-based laboratory tests assaying various prostate cancer biomarkers along with magnetic resonance imaging (MRI), with many additional diagnostics emerging.
In this article, urologists Scott E. Eggener, MD, and Stacy Loeb, MD, MSc, discuss the current applications for biomarkers and MRI, their impact on clinical practice, and future developments.
The biomarkers for prostate cancer with direct relevance to practicing urologists fall into several categories defined by the clinical scenario where they are used. They include tests for early detection to help the decision about having an initial or repeat biopsy after a previously negative result, tests providing information for risk stratification to guide initial management decisions in men newly diagnosed with clinically localized prostate cancer, and tests to help inform decisions about adjuvant radiation following radical prostatectomy. Not discussed in this article are prostate cancer biomarker tests used by medical oncologists to help with targeted treatment selection for existing metastatic disease.
The NCCN Guidelines Version 2.2016 for Prostate Cancer Early Detection recommends consideration of percent free PSA, Prostate Health Index (phi), and 4Kscore in men with a PSA >3.0 ng/mL who have not yet had a biopsy. Mi-Prostate Score (MiPS) and SelectMDx are other new tests that can be used to assist the decision of whether or not to perform an initial biopsy in men with an elevated PSA.
The current NCCN guidelines state percent free PSA, phi, 4Kscore, PCA3, and ConfirmMDx may also be considered for men who have had at least one prior negative biopsy and are thought to be at higher risk. SelectMDx, MiPS, or MRI of the prostate can also be used in this setting.
A greater percent of PSA circulating in the free form indicates a lower risk of prostate cancer and aggressive disease. The percent free PSA test has been around since the 1990s and is a widely available second-line testing option.
phi is a blood test that reports probability of having prostate cancer detected on biopsy based on measurement of total, free, and p2PSA ([-2]proPSA). Nomograms are available combining phi with other risk factors to predict aggressive prostate cancer.
4Kscore, also a blood test, measures free, total, and intact PSA along with human kallikrein 2 and takes into account age, digital rectal exam results, and prior biopsy status to calculate a percent likelihood of finding high-grade (Gleason ≥7) cancer on biopsy.
Prostate Cancer Antigen 3 (PCA3) is a urine test that assays for a noncoding, prostate tissue-specific RNA that is overexpressed in prostate cancer. It generates a score reflecting likelihood of a positive biopsy.
MiPS analyzes serum PSA plus PCA3 and the TMPRSS2:ERG gene in urine. It provides a quantitative risk of having prostate cancer detected on biopsy and of having potentially aggressive prostate cancer detected on biopsy.
SelectMDx is a urinary assay measuring mRNA levels of two genetic biomarkers that are associated with increased probability for high-grade prostate cancer. It reports the likelihood of detecting prostate cancer on biopsy and the probability for high- versus low-grade disease.
ConfirmMDx is an epigenetic test that analyzes prostate biopsy tissue from a previous biopsy for prostate cancer-associated DNA methylation changes in three genes and addresses the possibility of sampling error and cancer in the prostate missed by the biopsy needle.
For men diagnosed with prostate cancer who are deciding whether to choose treatment or active surveillance, there are three tissue-based tests available that can help inform management decisions. They are Prolaris, Oncotype DX, and Decipher Score.
Prolaris analyzes 46 cell cycle progression genes and also takes into account clinical parameters. It reports probability of 10-year mortality with conservative management or biochemical recurrence risk following treatment.
Oncotype DX analyzes 17 cancer-related genes and generates a categorical result of risk for unfavorable pathology, defined as primary Gleason pattern 4 or higher or extracapsular extension.
Decipher analyzes 22 genes corresponding to RNAs from coding and non-protein-coding regions of the genome and gives a score relating to likelihood of developing metastasis within 5 years after surgery. Decipher can also be used to help inform decisions about adjuvant versus salvage radiation therapy following radical prostatectomy.
Dr. Loeb, assistant professor of urology and population health at NYU School of Medicine, New York, said she considers the laboratory biomarkers that are used to refine initial biopsy decisions very helpful because they provide additional information and have higher specificity than total PSA.
Dr. Eggener, who is associate professor of surgery at the University of Chicago Medicine, concurred. “The introduction of PSA screening led to a dramatic reduction in the number of men dying from prostate cancer, but also a large number of men diagnosed with cancers unlikely to ever cause problems and unlikely to benefit from immediate treatment,” he said. “These new screening biomarkers outperform PSA as they capture all or nearly all cancers that are destined to cause problems while limiting the proportion of men who undergo biopsy.”
Dr. Eggener noted that biomarker testing has also been helpful for limiting unnecessary repeat biopsies.
Dr. Eggener“Whereas in the past, biopsy would be done routinely in a patient with a previous negative biopsy and ongoing clinical suspicion for prostate cancer, these newer biomarker tests provide risk stratification that can help determine if repeat biopsy is warranted,” he said.
Even though there is strong scientific rationale underlying all of the biomarker tests and solid clinical data to support their use, there are economic challenges for their integration into clinical practice, Dr. Eggener said.
“If the biomarker tests were cheap and easy, then they would be considered for nearly every patient. But such routine use does not seem appropriate because some of these tests are expensive and for many patients the results may not influence the decision one way or another,” he said. “Undoubtedly, there are situations when the biomarkers are so powerful that it makes the decision relatively simple and easy. However, a significant proportion of men are left with the same uncertainty they had before the biomarker results were available.”
Individual differences in risk tolerance help explain why the biomarker tests do not have a more definitive influence on management decisions, said Dr. Eggener, offering the following example to illustrate this point:
A healthy 60-year-old man with a normal prostate exam and no family history of prostate cancer has a PSA of 5.0 ng/mL. The patient is told the probability of finding prostate cancer on biopsy is probably 30% to 40%, and the likelihood of finding high-risk disease is significantly lower. The 4Kscore is ordered.
“If the result shows the man has a 1% chance of high-grade disease, he would probably be confident foregoing biopsy while he probably would not hesitate to choose biopsy if the 4Kscore indicated a 60% chance of finding high-grade cancer. However, the threshold at which an individual might choose or decline biopsy will vary,” Dr. Eggener said.
“When the 4Kscore shows there is a 7% chance of having high-grade prostate cancer, some men will definitely want a biopsy, some will be certain they do not need it, and others will still hem and haw.”
MRI to identify suspicious areas in the prostate is another option for supplementing decisions on whether to repeat a biopsy. According to a 2016 joint consensus statement from the AUA and Society of Abdominal Radiology, MRI should be strongly considered in a patient who is undergoing a repeat biopsy because of persistent clinical suspicion for prostate cancer. However, the decision whether to perform MRI must also take into account the results of other biomarkers, cost, and the availability of high-quality MRI images and interpretation.
Dr. Eggener, who was a member of the workgroup that developed the consensus statement, noted there are numerous studies showing the value of prostate MRI and MRI-targeted cores for improving the detection of clinically significant disease. In referring patients for MRI, however, urologists must keep in mind that “high-quality” MRI and MRI interpretation is essential to optimize the value of the information.
“When it comes to prostate imaging, an MRI is not an MRI is not an MRI. Quality of the imaging depends on the quality of the equipment, how the test is done, and the experience and expertise of the interpreting radiologist. Many centers have looked at their targeted biopsy results and published data for external review. An overwhelming majority of centers that do MRI of the prostate, however, do not know their internal quality and outcomes,” Dr. Eggener said.
Dr. LoebDr. Loeb noted that at NYU Langone, MRI is used routinely to provide a roadmap for targeting suspicious areas in men undergoing biopsy. She described its role as “transformative,” but she also cautioned that urologists need to consider the quality of the test and whether the institution where the MRI will be done has a quality assurance program for data tracking.
MRI is also being used fairly often to guide repeat biopsy in men with favorable-risk prostate cancer who are considering active surveillance, with data showing it improves detection of more aggressive cancers that might exclude a man from proceeding with active surveillance.
In addition, some data suggest a role for MRI prior to initial biopsy.
“Ongoing clinical trials will determine whether the use of MRI prior to considering a first biopsy is worthwhile. Currently it is not standard of care and should not be done routinely,” Dr. Eggener said.
Research to develop additional biomarkers for prostate cancer is continuing. The ExoDx Prostate IntelliScore, a novel urine exosome gene expression assay, is a newer test demonstrating utility for identifying high-grade prostate cancer. The Stockholm-3 Model (STHLM3) has shown promise for helping men to decide whether or not to undergo biopsy. It combines six plasma protein biomarkers, genetic polymorphisms, and clinical variables to estimate the risk of a Gleason Score ≥7 prostate cancer on biopsy.
Looking ahead, Dr. Loeb said she hopes growing experience and forthcoming data from clinical studies will provide insights for refining biomarker options in various clinical scenarios and in what order they might be done.
“For a patient who has a rising PSA with a previous negative biopsy, MRI along with blood, urine, and tissue tests are all options, but we don’t know which should come first and how best to integrate the markers with MRI,” she explained.
She pointed out there have also been very few head-to-head studies comparing the markers. “Results from head-to-head studies show the phi test and 4Kscore have similar performance, and phi is better than PCA3 for predicting clinically significant disease. However, there is a lack of evidence about the relative performance of most other biomarkers. Hopefully we will see results from more comparative studies in the future that will help better guide our care,” Dr. Loeb said.
Disclosures: Dr. Eggener has been a consultant, speaker, or investigator for OPKO, MDxHealth, Myriad Genetics, and Genomic Health. Dr. Loeb has received honoraria from Boehringer Ingelheim and MDxHealth, consulting fees from Lilly, and travel reimbursement from Minomic.
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